Candidate: My career goal is to be a research scientist addressing mechanisms underlying complicated behaviors in humans and animals under physiological and pathological conditions. I have a substantial record of accomplishment to demonstrate my pursuit of this goal. During my postdoctoral training at Yale, my work on the role of neurotransmitters, neuropeptides and neurotrophic factors in the modulation of neuronal activity in developing and mature hypothalamic neurons, led to peer-reviewed publications (including seven first-author papers and nine secondary author papers) in high quality journals. I was awarded career development grants/awards from the American Heart Association and the NIH. During the last seven years, I established my own independent research program and was awarded a R01 grant from the NIH to address cellular mechanisms underlying feeding regulation in the hypothalamus. We have demonstrated that neuronal plasticity in hypocretin neurons underlies energy homeostasis and sleep regulation, which has been published in high- impact peer-reviewed journals. In this application, I propose that through a period of rigorous research training outlined here, my research ability in basic behavioral science will be substantially enhanced and I will be capable to pursue a new direction (drug addiction) in my research. Environment: I am an Associate Professor in the Section of Comparative Medicine at Yale University School of Medicine. Yale University has provided an outstanding environment for career development during my pursuit to be an independent investigator. I feel that I will be able to take full advantage of the environment and resources here to achieve my goals outlined in this application. Research: Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. There is compelling evidence that drug addiction is a learned behavior. Mechanisms underlying learning and memory (experience-dependent neuroplasticity) in the normal brain are "hijacked" by addictive substances to produce an enduring and compelling urge to consume illicit drugs. The lateral hypothalamus (LH) has long been recognized to participate in the regulation of reward-related behaviors in animals. It is now clear that the hypocretin system participates in behaviors related to drug reward. It is not clear whether the experience-dependent neuroplasticity in hypocretin neurons is essential for the development of drug abuse. In this proposal, our chief hypothesis is that the experience-dependent plasticity in hypocretin neurons is essential for the expression of behaviors related to cocaine reinforcement. The specific aim is to determine whether cocaine self-administration results in enduring changes in synaptic strength of hypocretin glutamatergic inputs and to determine whether manipulations that abolish synaptic plasticity in hypocretin neurons alter cocaine reinforcement in animals. Relevance: Our long-term goal is to bridge the gap between clinical studies and basic research on the role of the CNS in cocaine addiction. The research training proposed in this application is highly relevant to the mission of the NIH and the OppNet. PUBLIC HEALTH RELEVANCE: Drug addiction has been considered a chronic disease and a risk factor for many other diseases and disorders. About 19.7 million Americans are current users of illicit drugs, which has posed a significant burden on the health care system, economy and society in the country. The long-term goal of this proposal is to bridge the gap between clinical studies and basic research on the role of the hypocretin system in cocaine addiction-related behaviors.